Abstract The prevalence of obstructive sleep apnea (OSA) is high in the Veteran population and the prevalence is increased further in Veterans with spinal cord injury. If not treated promptly, OSA may result in the development of numerous cardiovascular, neurocognitive and metabolic abnormalities. Thus, OSA is a major health concern in the Veteran population. However, treatment of OSA in many cases does not lead to significant improvements in outcome measures. This inadequacy may be a consequence of reduced treatment compliance with CPAP and/or because factors other than those directly linked to sleep apnea contribute to the presence of coincident co-morbidities. Consequently, innovative therapies that increase CPAP compliance and/or directly impact those co-morbidities typically associated with OSA independent of CPAP treatment could improve outcomes strongly linked to sleep apnea. My laboratory has established that mild intermittent hypoxia (IH) initiates sustained increases in chest wall and upper airway muscle activity in humans. This sustained increase is a form of respiratory plasticity known as long-term facilitation (LTF). Repeated daily exposure to mild IH that leads to the initiation of LTF of upper airway muscle activity could lead to increased stability of the upper airway. In line with my laboratory?s mandate to develop innovative therapies to treat sleep apnea, this increased stability could ultimately reduce the CPAP required to treat OSA and improve compliance with this gold standard treatment. Improved compliance could ultimately serve to mitigate those co-morbidities linked to sleep apnea. Moreover, in addition to improving CPAP compliance numerous studies indicate that mild intermittent hypoxia has many direct beneficial cardiovascular, neurocognitive and metabolic effects. Thus, mild intermittent hypoxia could serve as multipronged therapeutic approach to treat sleep apnea. In accordance with this postulation, Aim 1 of our proposal will determine if repeated daily exposure to mild IH serves as an adjunct therapy coupled with CPAP to mitigate associated co-morbidities via its direct effects on a variety of cardiovascular, metabolic and neurocognitive measures and indirectly by improving CPAP compliance. Modifications in autonomic (i.e. sympathetic nervous system activity) and cardiovascular (i.e. blood pressure) function will be the primary outcome measures coupled to secondary measures of metabolic and neurocognitive outcomes. Sleep is typically associated with a reduction in respiratory motoneuron excitability. This response is exacerbated and coupled to obstructive apneic events as a consequence of spinal cord injury induced morphological and neurological impairment of bulbospinal synaptic inputs to respiratory motoneurons, and adaptations in brainstem respiratory and upper airway motor function. These modifications are coupled to an incidence of sleep-disordered breathing (i.e. both central and obstructive sleep apnea) which is approximately 15 times higher in individuals with spinal cord injury than in the general population of the United States. Thus, exposure to this stimulus could improve CPAP compliance and enhanced outcome measures as outlined above. Additionally, repeated daily exposure to intermittent hypoxia promotes the recovery of respiratory and motor limb function in animals and humans. Thus, daily repeated exposure to IH could have significant therapeutic effects on respiratory and limb motor function in individuals with spinal cord injury accompanied by sleep apnea. Thus, Aim 2 of our proposal will serve to determine if IH can serve to mitigate co-morbidities linked to sleep apnea and promote the recovery of respiratory motor function during wakefulness and sleep, and motor limb function during wakefulness.